This revised program project focuses on the pathogenesis of Tourette's syndrome (TS) and obsessive compulsive disorder (OCD) as models for understanding the interplay of genetic, neurobiological and psychological factors during the course of CNS development. TS, OCD and related conditions are prevalent disorders affecting as many as 0.3 - 3% of the population. They are frequently chronic and associated with marked impairment and disability. Although clinical care has improved over the past decade, a significant number of patients fail to respond adequately or experience intolerable side effects. The etiology of these disorders is unknown. Compelling evidence suggests that the vulnerability to develop TS and OCD is mediated by both genetic and environmental factors, and that neural systems located in the basal ganglia and functionally related brain structures are involved in their pathogenesis. Based on explicit models of pathogenesis for TS and OCD, an array of clinical, neuropsychological, genetic, neurobiological and neuroimaging techniques have been selected. A major focus of the program project involves a detailed study of 440 probands, aged 7 to 50 years, and their first degree family members drawn from a regional referral base. All probands will be studied using clinical, neuropsychological, genetic, neurobiological and neuroimaging techniques. Subsets of these probands will also participate in a clinical trial and/or a CSF study. In addition, a sample of 200 affected sib pairs (TS = 100 and OCD = 100) and a set of ten large multigenerational kindreds (TS = 5, OCD = 5) will be selected from a larger referral base for genetic linkage and association studies. A series of interrelated neuropathological studies are also proposed using postmortem brain tissue from more than 20 TS patients and more than 40 controls. Molecular studies of the development of the basal ganglia and their intracellular signalling pathways are also proposed. These studies are divided into five projects and are supported by three cores.